Pharmaceutical composition comprising lidocaine and melatonin

ABSTRACT

The present disclosure provides a pharmaceutical composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof. The compositions of the present disclosure may find utility in treatment of mucositis, oral mucositis, ulcers, ulcer mediated pain and the like conditions. Aspects of the present disclosure also relates to method of treating oral and gastrointestinal disease/conditions using the advantageous compositions of the present disclosure.

TECHNICAL FIELD

The present disclosure generally relates to the field of pharmaceutical compositions. In particular, the present disclosure provides a pharmaceutical composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof. The compositions of the present disclosure may find utility in treatment of mucositis, oral mucositis, ulcers, ulcer mediated pain and the like conditions.

BACKGROUND

Pain is a warning signal, primarily protective in nature, but causes discomfort and suffering; may even be unbearable and incapacitating. It is the most important symptom caused by C, A-δ afferent fibers activation during tissue injury and inflammation. Histamine, serotonin, ROS, prostanoids and kinins are major inflammatory mediators involved in causing nociceptive and neuropathic pain.

Mucositis is the painful inflammation and ulceration of the mucous membranes lining the digestive tract, usually as an adverse effect of chemotherapy and radiotherapy treatment for cancer. Mucositis can occur anywhere along the gastrointestinal (GI) tract, but oral mucositis refers to the particular inflammation and ulceration that occurs in the mouth. Oral mucositis is a common and often debilitating complication of cancer treatment.

Current treatment options available for such oral and gastrointestinal disorders/conditions, in particular, for oral mucositis include non-pharmacological oral hygiene care, decontamination and pharmacological agents for example, systemic analgesics, topical palliative agents, oral rinses like 2% viscous lidocaine solution, magic mouthwash preparations, a topical morphine solution are used to control pain but still there is a need of effective pain management, and there is no statistically significant evidence to suggest that available mouthwashes are effective in pain relief (based on VAS score); further, opioids and anesthetic agents are associated with severe side effects like mouth dryness, loss of taste, dizziness, stomach discomfort and constipation and they are short lasting.

To solve the above problems, particularly, for treatment of oral and gastrointestinal disorders/conditions associated with oxidative stress, significant efforts have been put forth by the researchers to find products for treating oral and gastrointestinal disorders. However, none of the existing approaches seem to satisfy the existing needs. A need is also felt of improved formulations that are easy to administer and aids in improving patient compliance. The present disclosure satisfies the existing needs, at least in part, and overcomes one or more disadvantages of the conventional approaches.

OBJECTS

One of the objects of the present disclosure is to provide a pharmaceutical composition that may overcome the limitations associated with the conventional compositions.

Another object of the present disclosure is to provide a composition that exhibits superior storage stability and functional reciprocity.

Further object of the present disclosure is to provide a composition that is easy to prepare and is economical.

Yet another object of the present disclosure is to provide a pharmaceutical composition that delivers an immediate release or modify or control the delivery rate of different active agents present in the composition.

Still another object of the present disclosure is to deliver the active agents either simultaneously or concurrently or concomitantly to a subject for treatment of a disease.

SUMMARY

The present disclosure generally relates to the field of pharmaceutical compositions. In particular, the present disclosure provides a pharmaceutical composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof.

In an embodiment, the composition comprises Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof in a weight ratio ranging from 1:1 to 400:1. In an embodiment, the composition is a fixed dose combination.

In an embodiment, the composition comprises Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof in a weight ratio ranging from 5:1 to 150:1.

In embodiment, Lidocaine or salt or hydrates or solvates thereof is present in an amount ranging from 50 mg to 400 mg. In an embodiment, Melatonin or salt or hydrates or solvates thereof is present in an amount ranging from 1 mg to 60 mg.

In an embodiment, the composition includes: Lidocaine or salt or hydrates or solvates thereof in an amount ranging from 50 mg to 400 mg and Melatonin or salt or hydrates or solvates thereof in an amount ranging from 1 mg to 60 mg. In one embodiment, Lidocaine is present as Lidocaine hydrochloride monohydrate.

The composition also includes a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient is selected from any or a combination of: a diluent, an anti-oxidant, a preservative, an alkalizing agent, a buffering agent, a disintegrant, a binder, an anti-foaming agent, a solvent, a glidant, a lubricant, a flavoring agent, a coating agent, a rate controlling polymer or non-polymer, a zinc salt, a fatty acid or derivative thereof, an amino acid or metabolites or derivative thereof, a bulking agent, an anti-tacking agent, an emulsifier, a surfactant, a plasticizer and a stabilizer. In an embodiment, the fatty acid derivative includes any or a combination of: diglyceryl lauryl fumarate, diglyceryl lauryl succinate, and diglyceryl capryl succinate.

In an embodiment, there is disclosed a fixed dose pharmaceutical composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof. In an embodiment, the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises Lidocaine or salt or hydrates or solvates thereof, Melatonin or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises a pharmaceutically acceptable excipient.

In another embodiment, there is disclosed a fixed dose pharmaceutical composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises Melatonin or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises Lidocaine or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient.

In yet another embodiment, there is disclosed a fixed dose pharmaceutical composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises Lidocaine or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises Melatonin or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient.

In yet another embodiment, there is disclosed a fixed dose pharmaceutical composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises a pharmaceutically acceptable excipient, and the extra-granular portion comprises Lidocaine or salt or hydrates or solvates thereof, Melatonin or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient.

In an embodiment, the portions are compressed together to obtain any of: a tablet dosage form and a Lozenge dosage form, optionally coated with a seal coat. In an embodiment, the seal coat is an aqueous seal coat.

In yet another embodiment, the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises a pharmaceutically acceptable excipient, and the extra-granular portion comprises Lidocaine hydrochloride monohydrate in an amount of 100 mg, Melatonin in an amount of 10 mg and a pharmaceutically acceptable excipient.

In yet another embodiment, the composition comprises Lidocaine hydrochloride monohydrate in an amount of 100 mg, Melatonin in an amount of 10 mg and a pharmaceutically acceptable excipient, said composition being a directly compressed lozenge formulation.

In yet another embodiment, the composition comprises Lidocaine hydrochloride monohydrate in an amount of 100 mg, Melatonin in an amount of 3 mg and a pharmaceutically acceptable excipient, said composition being a directly compressed lozenge formulation.

In yet another embodiment, the composition comprises Lidocaine hydrochloride monohydrate in an amount of 200 mg, Melatonin in an amount of 3 mg and a pharmaceutically acceptable excipient, said composition being a directly compressed lozenge formulation.

DETAILED DESCRIPTION

The present disclosure generally relates to the field of pharmaceutical compositions.

As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art. It is also understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

It must be noted that, as used in this specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, “an active agent” or “an active ingredient” refers not only to a single active agent but also to a combination of two or more different active agents, “a dosage form” refers to a combination of dosage forms as well as to a single dosage form, and the like.

The term “active agent” or “therapeutic agent”, encompass not only the specified molecular entity but also its pharmaceutically acceptable, pharmacologically active analogs, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds.

The term “combination therapy” or “combined treatment” or “in combination” as used herein denotes any form of concurrent or concomitantly or co-administration of active agents for treating mucositis, oral mucositis, ulcers, ulcer mediated pain and the like oral and gastrointestinal diseases/conditions.

The terms “treating” and “treatment” as used herein refers to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, and improvement or remediation of damage caused thereby. Thus, “treating” a subject/patient as described herein encompasses treating oral, gastrointestinal and esophageal diseases. The ulcers and gastrointestinal disease as disclosed herein includes peptic ulcers that are chronic lesion or painful sores or seen on the lining of gastrointestinal tracts due to aggressive action of gastric-peptic juices. Peptic ulcer in the stomach is called a gastric ulcer and in the duodenum is called duodenal ulcer. The ulcers are caused because of imbalance between defensive mechanism of gastric mucosa (epithelial cells lining, secretion of bicarbonate and mucus), and aggressive factors (use of NSAIDs, corticosteroids, H. pylori infection, secretion of pepsin, gastric acid, smoking, alcohol). Gastroesophageal reflux disease (GERD) or peptic esophagitis or reflux esophagitis is a clinical condition in which the reflux of stomach acid into the esophagus impacts a subject's normal functioning or to cause damage to the esophagus, gastritis, odynophagia, or painful swallowing, and dysphagia, regurgitation of food, belching, nausea, vomiting and sore throat. Further gastric esophagitis and related diseases such as esophageal tumor, gastrointestinal symptoms, chronic pharyngitis, inflammation mediated pain, ulcers mediated pain, Barrett's esophagus, esophageal adenocarcinoma, GERD-related pulmonary symptoms, oral, gastrointestinal diseases, inflammation, gastric cancer, neoplasm mediated secretions, esophagus related neoplasm, oral inflammation, head and neck cancer related oral and gastrointestinal complications, covid-19, cytokine storms, effectively in short time. Furthermore, oral and gastrointestinal diseases including oral mucositis, oral ulcers, peptic ulcers, gastric ulcer, duodenal ulcer, esophageal ulcers, gastroesophageal reflux disease (GERD), inflammation, allergy, stomatitis, insomnia, gastric cancer, Covid-19, cytokine mediated inflammation, severe erosive esophagitis, pressure ulcers, their associated symptoms and Zollinger Ellison syndrome. Mucositis is the painful inflammation and ulceration of the mucous membranes lining the digestive tract, usually as an adverse effect of chemotherapy and radiotherapy treatment for cancer. Mucositis can occur anywhere along the gastrointestinal (GI) tract, but oral mucositis refers to the particular inflammation and ulceration that occurs in the mouth. Oral mucositis is a common and often debilitating complication of cancer treatment. Use in treating ulcers in subjects with human immunodeficiency virus (HIV) infection and sars-cov-2 infection. HIV patients suffer from persistent, painful ulcers seen on the soft palate, buccal mucosa, tonsillar area or tongue, which are referred to as aphthous ulcers. Such conditions are more or less associated with painful sensation, either acute or chronic. The compositions of the present disclosure, although preferably, may be used for treatment of such painful oral and gastrointestinal conditions, the same may be used for other such conditions as well, wherein relieving pain in a subject and/or remediation/reversal of oxidative stress to prevent and/or cure the underlying disorder associated with heightened oxidative stress in a subject.

The term “dosage form” denotes any form of a pharmaceutical composition that contains an amount of active agent sufficient to elicit a desired therapeutic response.

The term “controlled release” refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate. The term “controlled release” as used herein includes sustained release, non-immediate release and delayed release formulations.

The term “sustained release” (synonymous with “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time.

The term “pharmaceutically acceptable” means the material incorporated into a pharmaceutical composition that can be administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. When the term “pharmaceutically acceptable” is used to refer to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.

“Pharmacologically active” (or simply “active”) as in a pharmacologically active derivative or analog, refers to a derivative or analog having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.

The present disclosure provides a pharmaceutical composition comprising: Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof. In an embodiment, the composition is a fixed dose combination. The compositions of the present disclosure may find utility in treatment of mucositis, oral mucositis, ulcers, ulcer mediated pain and the like conditions.

In an embodiment, the composition comprises Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof in a weight ratio ranging from 1:1 to 400:1.

In an embodiment, the composition comprises Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof in a weight ratio ranging from 5:1 to 150:1.

In an embodiment, the composition comprises Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof in a weight ratio ranging from 7.5:1 to 150:1.

In an embodiment, the composition comprises Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof in a weight ratio ranging from 8:1 to 100:1.

In an embodiment, the composition comprises Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof in a weight ratio ranging from 9:1 to 75:1.

In an embodiment, the composition comprises Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof in a weight ratio of 10:1.

In an embodiment, the composition comprises Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof in a weight ratio of 100:3.

In an embodiment, the composition comprises Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof in a weight ratio of 200:3.

In embodiment, Lidocaine or salt or hydrates or solvates thereof is present in an amount ranging from 50 mg to 400 mg. In an embodiment, Melatonin or salt or hydrates or solvates thereof is present in an amount ranging from 1 mg to 60 mg.

In an embodiment, Lidocaine or salt or hydrates or solvates thereof is present in the composition in an amount of 50 mg to 400 mg. Alternatively, Lidocaine or salt or hydrates or solvates thereof is present in an amount of 60 mg to 300 mg. Alternatively, Lidocaine or salt or hydrates or solvates thereof is present in an amount of 70 mg to 250 mg. Still alternatively, Lidocaine or salt or hydrates or solvates thereof is present in an amount of 90 mg to 250 mg. In an embodiment, the amount of Lidocaine or salt or hydrates or solvates thereof in the composition is 100 mg. In an embodiment, the amount of Lidocaine or salt or hydrates or solvates thereof in the composition is 200 mg. In an embodiment, Lidocaine is present as Lidocaine hydrochloride monohydrate.

The composition includes Melatonin or salt or hydrates or solvates thereof in an amount ranging from 1 mg to 60 mg. Alternatively, Melatonin or salt or hydrates or solvates thereof is present in an amount of 1 mg to 40 mg. Alternatively, Melatonin or salt or hydrates or solvates thereof is present in an amount of 1 mg to 15 mg. Still alternatively, Melatonin or salt or hydrates or solvates thereof is present in an amount of 2 mg to 12 mg. In an embodiment, the amount of Melatonin or salt or hydrates or solvates thereof in the composition is 3 mg. In an embodiment, the amount of Melatonin or salt or hydrates or solvates thereof in the composition is 10 mg.

In an embodiment, either of the two drug actives melatonin or lidocaine are given simultaneously as individual formulations/compositions or two drug actives are given in a combination to a subject suffering from a disease.

In another embodiment, lidocaine and melatonin are given simultaneously as individual formulations/compositions or lidocaine and melatonin are given in a combination to a subject suffering from a disease.

In another embodiment, active agents lidocaine and melatonin are formulated as individual formulations/compositions in titrated strengths or binary mixture compositions or a fixed dosage combination for the treatment of a disease/condition in a human subject.

In an embodiment, melatonin and lidocaine are given simultaneously as individual formulations or compositions. In another embodiment, melatonin and lidocaine are given concomitantly as individual formulations/compositions or the two active agents melatonin and lidocaine are given in a combination to a subject.

The composition also includes a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient may be selected from any or a combination of: a diluent, an anti-oxidant, a preservative, an alkalizing agent, a buffering agent, a disintegrant, a binder, an anti-foaming agent, a solvent, a glidant, a lubricant, a flavoring agent, a sweetener, a coating agent, a rate controlling polymer or non-polymer, a zinc salt, a fatty acid or derivative thereof, an amino acid or metabolites or amino acid derivatives, a bulking agent, an anti-tacking agent, an emulsifier, a surfactant, a plasticizer and a stabilizer.

In an embodiment, the diluent(s) include(s), but not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, and magnesium aluminum silicate and mixtures thereof.

In an embodiment, the anti-oxidant(s) and preservative(s) include(s), but not limited to, L-Carnosine, vitamin A, vitamin E, vitamin C, D-Panthenol, retinyl palmitate, and selenium, citric acid, sodium citrate, methyl paraben, propyl paraben, p-hydroxybenzoic acid esters, sorbic acid, benzoic acid, propionic acid or salts thereof; Alcohols such as benzyl alcohol, butanol or ethanol, isopropyl alcohol, and quaternary ammonium compounds such as benzalkonium chloride, sodium benzoate and mixtures thereof.

In an embodiment, the alkalizing agent(s) include(s), but not limited to, ammonia solution NF, Ammonium Carbonate NF, Diethanolamine NF, monoethanolamine, Potassium Hydroxide NF, Sodium Bicarbonate USP, Sodium Borate NF, Sodium Carbonate NF, Sodium Hydroxide NF, sodium Phosphate Dibasic USP, trolamine NF, calcium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium trisilicate, aluminum hydroxide, aluminum carbonate, magnesium aluminium silicate hydrate, potassium bicarbonate, sodium bicarbonate, sodium citrate, potassium citrate, aluminum sulfate, calcium carbonate and mixtures thereof.

In an embodiment, the buffering agent(s) include(s), but not limited to, a bicarbonate salt of alkali earth metal, amino acids, an acid salt of an amino acid, an alkali salt of an amino acid and mixture thereof.

In an embodiment, the disintegrant(s) include(s), but not limited to Croscarmellose sodium, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, alginic acid and alginates, modified starches, sodium starch glycolate, sodium carboxy methyl cellulose, carboxymethyl cellulose calcium, polyvinylpyrrolidone, docusate sodium, guar gum and mixtures thereof.

In an embodiment the binder(s) include(s), but not limited to, hypromellose (or hypromellose 5 cps), polyvinyl pyrrolidone, copolymers of vinyl pyrrolidone with other vinyl derivatives, hydroxypropyl cellulosic derivatives (such as methylcellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylcellulose etc), polyacrylates (such as Carbopol, polycarbophil, etc), Povidone (all grades), Polyox of any molecular weight or grade, irradiated or not, maize starch, povidone, copovidone, corn starch, starch, polyvinylpyrrolidone (PVP), microcrystalline cellulose, powdered acacia, gelatin, guar gum, carbomer such as carbopol, polymethacrylates, starch, heavy magnesium oxide and mixtures thereof.

In an embodiment the anti-foaming agent(s) include(s), but not limited to, alcohols such as cetostearyl alcohol, insoluble oils such as castor oil, stearates, polydimethylsiloxanes and other silicones derivatives, ethers, paraffin oil, paraffin wax, glycols, simethicone (or simethicone 30% emulsion) and mixtures thereof.

In an embodiment, solvent(s) include(s), but not limited to, methanol, ethanol, n-propanol, isopropanol, hexane, heptane, petroleum ether, cyclohexane, diethyl ether, diisopropyl ether, ethyl acetate, methyl acetate, ethyl formate, methyl formate, isobutyl acetate, n-butyl acetate, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, acetone, ethyl methyl ketone, diisobutyl ketone, methyl isobutyl ketone, 1,4-dioxane, toluene, ammonia solution, glacial acetic acid, ammonium hydroxide, sodium hydroxide, calcium hydroxide, calcium carbonate, potassium hydroxide, potassium carbonate, water and mixtures thereof.

In an embodiment, the glidant(s) include(s), but are not limited to, colloidal silicon dioxide, stearic acid, talk, aluminium silicate and mixtures thereof.

In an embodiment, the lubricant(s) include(s), but not limited to, stearic acid, magnesium stearate, sodium stearyl fumarate, sodium lauryl sulphate, magnesium lauryl sulphate, fumaric acid, glyceryl palmitostearate, zinc stearate, calcium stearate, silica, talc, polyethylene glycol, paraffin and mixtures thereof.

In an embodiment, the flavoring agent(s) include(s), but not limited, cherry, maple, pineapple, orange, raspberry, banana-vanilla, peppermint, butterscotch, strawberry, vanilla, apricot, cinnamon, honey, lime, peach-orange, peach-rum, raspberry, wild cherry, mint and mixtures thereof.

In an embodiment, coating agent(s) include(s), but not limited to, Cellulosics, such as hydroxypropyl methyl cellulose (HPMC), methy ethylcellulose (MEC), carboxymethyl cellulose (CMC), carboxymethyl ethylcellulose (CMEC), hydroxyethyl cellulose (HEC), Hydroxypropyl cellulose (HPC), cellulose acetate phthalate (CAP), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hypromellose, povidone, copovidone, and ethyl cellulose (EC); Vinyls, such as polyvinyl alcohol; Acrylics, such as methacrylic acid/ethylacrylate copolymers (often used for enteric or delayed release coatings), Natural derivatives, such as shellac or alginate and mixtures thereof.

In an embodiment, the rate controlling polymer(s) include(s), but not limited to, cellulose acetate, alkyl celluloses, hydroxyalkyl, acrylic polymers, copolymers dialkylphthalates, dibutyl phthalate, microcrystalline wax and mixtures thereof.

In an embodiment, the rate controlling non-polymer(s) include(s), but not limited to, fat, wax, fatty acid, fatty acid ester, long chain monohydric alcohol or their ester and mixtures thereof.

In an embodiment, zinc salt(s) include(s), but not limited to, zinc oxide, zinc stearate, zinc L-carnosine, zinc acetate, zinc chloride, zinc bromide, zinc fluoride, zinc hexafluorosilicate, zinc iodide, zinc molybdate, zinc nitrate, zinc molybdite, zinc oxalate, zinc perchlorate, zinc tetrafluoroborate, zinc sulfate and mixtures thereof.

In an embodiment, the fatty acid(s) or derivatives thereof include(s), but not limited to, fatty acids with C1 to C30 carbons, which includes long chain fatty acids; saturated or unsaturated fatty acids and derivatives thereof (monounsaturated fatty acids (MUFAs) C18:1n-12c, C16:1n-5, C16:4n-1 and the polyunsaturated fatty acids (PUFAs) C16:3n-4, C20:3n-3, C20:4n-6, C21:5n-3 and C18:2n-9c,12t); hydrogenated fatty acids; fatty acid glycerides; polyoxyethylated oleic glycerides; monoglycerides and diglycerides; mono-, bi- or tri-substituted glycerides; glycerol mono-oleate esters; glycerol mono-caprate; glyceryl monocaprylate; dicaprylate; laurate, monolaurate; glyceryl palmitostearate; glyceryl behenate; diethyleneglycol palmitostearate; polyethyleneglycol stearate; polyoxyethyleneglycol palmitostearate; glyceryl mono palmitostearate; cetyl palmitate; polyethyleneglycol palmitostearate; dimethylpolysiloxane; mono- or di-glyceryl behenate; fatty acid derivatives such as diglyceryl lauryl fumarate (DGLF), diglyceryl lauryl succinate, diglyceryl capryl succinate, diglyceryl capryl fumarate; fatty alcohols associated with polyethoxylate fatty alcohols; cetyl alcohol; octyldodecanol; myristyl alcohol; isopropyl myristate, isopropyl palmitate, stearic acid, lauric acid, EPA, DHA, linoleic acid, linolenic acid, stearyl alcohol and mixture thereof. In an embodiment, the fatty acid derivatives includes any or a combination of: diglyceryl lauryl fumarate (DGLF), diglyceryl lauryl succinate, diglyceryl capryl succinate, and diglyceryl capryl fumarate, and the same can be used in the composition to either delay disintegration and/or absorption and thereby provide sustained action over a longer period.

In an embodiment, the amino acids or metabolites or amino acid derivatives include(s), but not limited to, glycine, glutamine, asparagine, arginine, lysine in biologically active enantiomeric forms, L-carnosine, L-carnitine, choline, betaine, taurine, glycosaminoglycans including hyaluronic acid, chondroitin sulfate, glucosamine, L-glucosamine, heparins and mixtures thereof.

In an embodiment, the bulking agent(s) include(s), but not limited to, lactose USP, Starch 1500, mannitol, erythritol, sorbitol, maltodextrin, maltitol or other non-reducing sugars; microcrystalline cellulose (e.g., Avicel), dibasic calcium phosphate (anhydrous or dihydrate), sucrose, etc. and mixtures thereof.

In an embodiment, the anti-tacking agent(s) include(s), but not limited to, stearates; stearic acid; vegetable oil; waxes; a blend of magnesium stearate and sodium lauryl sulfate; sodium benzoate; sodium acetate and mixtures thereof.

In an embodiment, the surfactant(s) and emulsifier(s) include(s), but not limited to, ionic or non-ionic surfactants and emulsifiers, poloxamers, polyethylene glycols, polyethylene glycol monostearate, polysorbates, sodium lauryl sulfate, polyethoxylated, hydrogenated castor oil and mixtures thereof.

In an embodiment, the plasticizer(s) include(s), but are not limited to, diethyl phthalate, triethyl citrate, acetyl tributyl citrate, dibutyl phthalate, triacetin, propylene glycol, polyethylene glycol, dichloromethane, acetone, ethanol, methanol, isopropyl alcohol, water and mixtures thereof.

In an embodiment, the stabilizer(s) include(s), but not limited to, gums, agar, taste masking agents like acrylic polymers, copolymers of acrylates, celluloses, resins and mixtures thereof.

In an embodiment, the sweetener(s) include(s), but not limited to, mannitol, sorbitol, polyethylene glycol (PEG) 6000 and 8000, Emdex, Nu-tab, Sweetrex, Mola-tab, Hony-tab, Sugartab, non-sugar sweetening agents such as aspartame, sorbitol, xylitol, isomalt, saccharin, sodium saccharin, calcium saccharin, sucralose, acesulfame-K, steviol, steviosin, mannitol, erythritol, lactitol, and sugar sweetening agents such as sucrose, fructose, dextrose and mixtures thereof.

Although several embodiments of the present disclosure names few of the commonly used excipients, any other excipient known to or appreciated by a skilled person can also be used to realize the advantageous compositions of the present disclosure. Examples of useful excipients which can optionally be added to the composition are described in the Handbook of Pharmaceutical Excipients, 3rd edition, Edited by A. H. Kibbe, Published by: American Pharmaceutical Association, Washington D.C., ISBN: 0-917330-96-X, and in Handbook of Pharmaceutical Excipients (4th edition), Edited by Raymond C Rowe—Publisher: Science and Practice.

Depending on the intended mode of administration, the pharmaceutical composition may be formulated as a solid, semi-solid or liquid dosage form. Non-limiting examples of dosage forms includes tablet, lozenge, capsule, caplet, modified release tablet or lozenge, suspension, solution, emulsion, suppository, granules, pellets, beads, powder, aerosol sprays (oral, nasal, dermal), cream, ointment, lotion, patches, pre-filled syringe, pre-filled pen, gel, tablet in tablet, bilayer tablet, trilayer tablet, inlay tablet, capsule in capsule, tablet(s) in capsule, granules and/or pellets in capsule, pellets and tablet in capsules and the likes.

In an embodiment, there is disclosed a fixed dose pharmaceutical composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof, wherein the composition is formulated into a chewy or hard or caramel based lozenge, pastilles, troches, soft lozenge, center or liquid filled lozenge, power based lozenge, compressed lozenge, syrup based lozenge, granulated lozenge, buccal and sublingual tablets. The lozenge formulation of the present disclosure may increase bioavailability, and affords immediate relief from pain. Lozenge dosage forms are easy to administer for geriatric and pediatric patients who can't swallow tablets formulation. This formulation may help to keep the drug in contact to the oral cavity for longer time. The lozenge may be formulated as a modified release formulation (modified release can be controlled release, immediate release, phased release, timed release, sustained release, delayed release or a combination of immediate or quick or fast and sustained or slow or extended release). The lozenge can be formulated as a bi-layer, tri-layer tablet or multi-layer tablet to facilitate the delivery of at least two or more active agents.

Typically, the carrier material for lozenge preparation includes sugar such as sucrose, dextrose, etc. Recently consumers have become concerned about the excessive levels of sugar contained within their diets. This concern has caused a demand for sugar-free products, including sugar-free medications. Pharmaceutical manufacturers have attempted to find alternative carrier bases in order to provide sugar-free lozenges. One such alternative carrier is a polyhydric alcohol such as xylitol. Polyhydric alcohols are considered as a viable alternative because they provide a sweet taste will mask the bitter taste of many medicinal agents. Lozenges made from polyhydric alcohols do suffer from one serious disadvantage. They dissolve very rapidly when placed in the oral cavity. For example, a lozenge made from a xylitol based carrier will dissolve completely within approximately 3 minutes of administration. Other polyhydric alcohols such as sorbitol or mannitol will also dissolve within 3 minutes of administration. Thus the medicinal agents are released so rapidly that a large percentage of the dose is washed into the patient's alimentary canal rather than having an opportunity to come in contact with the tissues of the oral cavity, which are under treatment. Thus, it would be a valuable contribution to the art to produce polyhydric alcohol based lozenges having slower rates of dissolution within the oral cavity.

In an embodiment, non-limiting examples of excipients for preparing a compressed powder lozenge or compressed granulated lozenge, cast lozenge includes at least one diluents, at least one fillers, at least one glidants, at least one lubricants, at least one binders, at least one preservatives, at least one artificial or natural sweeteners or and at least one aroma or flavoring compounds.

The lozenge may be formulated as a modified release formulation (modified can be controlled release, immediate release, phased release, timed release, sustained release, delayed release or a combination of immediate or quick or fast and sustained or slow or release). The lozenge can be formulated as a bi-layer, tri-layer tablet or multi-layer tablet to facilitate the delivery of at least two or more active agents.

In some embodiments, the compositions are formulated as cast lozenges comprising at least one base selected from fructo-oligosaccharides, crystalline sugar, candy base, isomalt or stevia; at least one aromas selected from natural aroma, essential oils such as citrus, mint oils, terpenes and sesquiterpenes, organic acids, alcohols, aldehydes, liquorice powder, menthol, peppermint oil or any fruit flavors; at least one taste enhancing ingredient such as saccharose, glutamic acid, E621 monosodium glutamate, MSG, E622 monopotassium glutamate, E623 calcium diglutamate, E625 Magnesium diglutamate); guanylic acid (a ribonucleotide) and its salts (E626 guanylic acid, E627 disodium guanylate, sodium guanylate, E628 dipotassium guanylate, E629 calcium guanylate); E630 inosinic acid, E631 disodium inosinate, E632 dipotassium inosinate, E633 calcium inosinate), E634 calcium 5′-ribonucleotides, E635 disodium 5′-ribonucleotides; E636 maltol, E637 ethyl maltol, E640 glycine and E641 L-leucine.

The advantages of drugs administration by the buccal route is the drug is not damaged by acidic media of the stomach, and the achievement of therapeutic serum concentrations of the drug more rapidly. The sublingual route gives greater permeability and has rich blood supply leading to more rapid absorption than other routes.

In an embodiment, there is disclosed a fixed dose pharmaceutical composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof, wherein the composition is formulated into a tablet dosage form. The tablet may be a monolayer tablet comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof distributed uniformly. The tablet may be a bilayer tablet comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof in any of a first layer and a second layer. Alternatively, the tablet may be a trilayer tablet comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof in any of a first layer, a second layer and a third layer. Alternatively, the tablet may be a press-coated tablet, i.e. a small tablet and a granulation or a blend is compressed together to one large press-coated tablet. All types of the tablets mentioned hereinbefore may be without a coating or may have one or more coatings, in particular film-coatings.

The tablet-in-tablet dosage form may be prepared by compressing active ingredients with one or more rate controlling polymer or non-polymer to form a core extended release tablet; and compressing active ingredients optionally along with one or more pharmaceutically acceptable excipient onto said core tablet to form compressed tablet that causes immediate release of the active ingredients.

In another embodiment of the present invention, the pharmaceutical composition is formulated as an inlay tablet. Inlay tablets are tablets, wherein inner tablet is positioned within a comparatively larger outer tablet in such a way that at least one surface of the inner tablet is not in contact with outer tablet. Inlay tablet dosage form includes: (a) an inner inlayed tablet comprising active ingredients and excipient(s) that causes extended release; and (b) an outer tablet comprising active ingredients along with excipient(s) to cause immediate release.

In another embodiment, the present disclosure embraces capsule-in-capsule formulations, wherein smaller size capsule is encapsulated into a larger capsule. Capsule-in-capsule consists of an external capsule and internal capsule (inner capsule) located therein. It is preferred that smaller size capsule is filled with active ingredients and excipients so as to cause extended release while larger capsule is filled, optionally, with active ingredients along with excipients for immediate release.

The tablet of the present disclosure may be monolithic that means having a homogenous matrix of active ingredient and pharmaceutically acceptable excipients. Alternatively, the tablet may be formed as a bilayer, wherein the one layer is having active ingredients along with pharmaceutically acceptable excipients and other layer is having pharmaceutically acceptable excipients. Alternatively, both layers of bilayer tablet may contain active ingredients.

The composition can be made by different manufacturing processes such as by direct compression wet granulation, dry granulation, melt granulation, melt congealing process, extrusion and the likes. The composition cores may be mono or multi-layer(s) and can be coated with appropriate overcoats as known in the art. Wet granulation involves formation of granules using active ingredient and/or one or more pharmaceutically acceptable excipients and this portion can be termed as intra-granular portion. These granules are then lubricated with active ingredient and/or a blend of excipients comprising lubricant and this lubricant blend is then compressed to form a tablet. The portion outside the granules can be referred as extra-granular portion. Direct compression on the other hand requires only that the active ingredient is blended with one or more pharmaceutically acceptable excipients before compression and then compressed into tablet.

In an embodiment, there is disclosed a fixed dose pharmaceutical composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises Lidocaine or salt or hydrates or solvates thereof, Melatonin or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises a pharmaceutically acceptable excipient.

In another embodiment, there is disclosed a fixed dose pharmaceutical composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof, wherein the composition comprises an intra-granular portion and an extra-granular portion, and wherein the intra-granular portion comprises Lidocaine or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises Melatonin or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient.

In yet another embodiment, there is disclosed a fixed dose pharmaceutical composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof, wherein the composition comprises an intra-granular portion and an extra-granular portion, and wherein the intra-granular portion comprises Melatonin or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises Lidocaine or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipients.

In yet another embodiment, there is disclosed a fixed dose pharmaceutical composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof, wherein the composition comprises an intra-granular portion and an extra-granular portion, and wherein the intra-granular portion comprises a pharmaceutically acceptable excipient, and the extra-granular portion comprises Lidocaine or salt or hydrates or solvates thereof, Melatonin or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient.

In an embodiment, the portions are compressed together to obtain any of: a tablet dosage form and a Lozenge dosage form, optionally coated with a seal coat. In an embodiment, the seal coat is an aqueous seal coat.

In an embodiment, the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises Lidocaine hydrochloride monohydrate in an amount of 100 mg, Melatonin in an amount of 10 mg and a pharmaceutically acceptable excipient, and the extra-granular portion comprises a pharmaceutically acceptable excipient.

In yet another embodiment, the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises a pharmaceutically acceptable excipient, and the extra-granular portion comprises Lidocaine hydrochloride monohydrate in an amount of 100 mg, Melatonin in an amount of 10 mg and a pharmaceutically acceptable excipient.

In yet another embodiment, the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises a pharmaceutically acceptable excipient, and the extra-granular portion comprises Lidocaine hydrochloride monohydrate in an amount of 100 mg, Melatonin in an amount of 3 mg and a pharmaceutically acceptable excipient.

In yet another embodiment, the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises a pharmaceutically acceptable excipient, and the extra-granular portion comprises Lidocaine hydrochloride monohydrate in an amount of 200 mg, Melatonin in an amount of 3 mg and a pharmaceutically acceptable excipient.

All types of the tablets mentioned hereinabove may be without a coating or may have one or more coatings, in particular film-coatings. A film coating is useful in limiting photolytic degradation and/or in limiting degradation of moisture sensitive materials.

In one embodiment, the tablet may be coated to delay disintegration and absorption and thereby provide sustained action over a longer period. The non-limiting examples of film coating includes glyceryl monostearate or glyceryl distearate, polyvinyl alcohol based, hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyethelene glycol 4000 and cellulose acetate phthalate film coating.

In yet another embodiment, there is disclosed a fixed dose pharmaceutical composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof, wherein the composition comprises Lidocaine hydrochloride monohydrate in an amount of 100 mg, Melatonin in an amount of 10 mg and a pharmaceutically acceptable excipient, said composition being a directly compressed lozenge formulation.

In yet another embodiment, there is disclosed a fixed dose pharmaceutical composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof, wherein the composition comprises Lidocaine hydrochloride monohydrate in an amount of 200 mg, Melatonin in an amount of 3 mg and a pharmaceutically acceptable excipient, said composition being a directly compressed lozenge formulation.

In yet another embodiment, there is disclosed a fixed dose pharmaceutical composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof, wherein the composition comprises Lidocaine hydrochloride monohydrate in an amount of 100 mg, Melatonin in an amount of 3 mg and a pharmaceutically acceptable excipient, said composition being a directly compressed lozenge formulation.

The compositions realized in accordance with embodiments of the present disclosure can find utility in treatment of mucositis, oral mucositis, gastritis, peptic ulcers, gastric ulcer, duodenal ulcer, esophageal ulcer, stomatitis, gastroesophageal reflux disease (GERD), esophagitis, Zollinger Ellison syndrome and the like oral and gastrointestinal conditions. Without wishing to be bound by the theory, it is believed that the combination of Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof, in particular, the fixed dose compositions disclosed herein, afford treatment of mucositis, oral mucositis, ulcers, ulcer mediated pain and the like conditions from root cause by relieving pain, by increasing the expression and by increasing the activity of endogenous antioxidant enzymes. The compositions of the present disclosure also provide improved pain relief in radiation induced oral mucositis, and also reduces the usage of opioids such as Morphine. Preliminary study on assessment of anti-oxidant, sedation and pain relief effects revealed marked improvement therein establishing the efficacy of the presently disclosed compositions. It could also be noted that the components of the compositions realized in accordance with embodiments of the present disclosure exhibit high degree of functional reciprocity by targeting different pathways and consequently, afford unique treatment options for mucositis, oral mucositis, ulcers, ulcer mediated pain and the like conditions. Without wishing to be bound by the theory, it is also believed that the compositions realized in accordance with embodiments of the present disclosure exhibit high degree of functional reciprocity, wherein one or more active agents of the composition aids in retarding metabolism of the other active agent(s), and consequently, may reduce the dosage requirements and/or may aid in affording a prolonged action/efficacy. Specifically, it is believed that melatonin undergoes metabolism through Cytochrome P450 system (CYP1A1), metabolism whereof can be decreased when combined with lidocaine.

Accordingly, an embodiment of the present disclosure provides a method of treatment of an oral condition in a subject, said method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof. The oral condition may be ulcer, ulcer mediated pain, oral mucositis and the like conditions associated with pain and/or caused by or associated with heightened oxidative stress.

Another embodiment of the present disclosure provides a method of treatment of a gastrointestinal condition, said method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof. The gastrointestinal condition may be ulcer, ulcer mediated pain, mucositis and the like conditions associated with pain and/or caused by or associated with heightened oxidative stress (such as by radiotherapy, chemotherapy etc.).

Further embodiment of the present disclosure provides a pharmaceutical composition for use in treatment of an oral condition, said composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof. The oral condition may be ulcer, ulcer mediated pain, oral mucositis and the like conditions associated with pain and/or caused by or associated with heightened oxidative stress.

Still further embodiment of the present disclosure provides a pharmaceutical composition for use in treatment of a gastrointestinal condition, said composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof. The gastrointestinal condition may be ulcer, ulcer mediated pain, mucositis and the like conditions associated with pain and/or caused by or associated with heightened oxidative stress (such as by radiotherapy, chemotherapy etc.).

Yet another embodiment of the present disclosure provides use of a pharmaceutical composition for manufacture of a medicament for treatment of an oral condition, said composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof. The oral condition may be ulcer, ulcer mediated pain, oral mucositis and the like conditions associated with pain and/or caused by or associated with heightened oxidative stress.

Yet another embodiment of the present disclosure provides use of a pharmaceutical composition for manufacture of a medicament for treatment of a gastrointestinal condition, said composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof. The gastrointestinal condition may be ulcer, ulcer mediated pain, mucositis and the like conditions associated with pain and/or caused by or associated with heightened oxidative stress (such as by radiotherapy, chemotherapy etc.).

Further embodiment of the present disclosure provides a pharmaceutical composition for treatment of an oral condition, said composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof. The oral condition may be ulcer, ulcer mediated pain, oral mucositis and the like conditions associated with pain and/or caused by or associated with heightened oxidative stress.

Further embodiment of the present disclosure provides a pharmaceutical composition for treatment of a gastrointestinal condition, said composition comprising Lidocaine or salt or hydrates or solvates thereof and Melatonin or salt or hydrates or solvates thereof. The gastrointestinal condition may be ulcer, ulcer mediated pain, mucositis and the like conditions associated with pain and/or caused by or associated with heightened oxidative stress (such as by radiotherapy, chemotherapy etc.).

The compositions of the present disclosure affords increased therapeutic effects, and reduced adverse effects, making these pharmaceutical compositions extremely effective therapeutics, especially in the treatment of oral, gastrointestinal/esophageal disorders or diseases. Therapeutic levels of the combined drugs will vary from individual to individual and progression stage of disease. The combination medications in the appropriate amounts and intervals effective to treat oral, gastrointestinal/esophageal disorders or diseases will necessarily be monitored both clinically and chemically by the medical experts or trained physicians. The relevant formulation can eventually take the form of a combined pill given daily, a daily or weekly patch, a long-term injection, an implant, or a short-acting or long-acting form of medication.

Further, the patient may receive the specific dosage over a period of weeks, months, or years. For example, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5 years and the like.

The choice of appropriate dosages for the drugs used in combination therapy according to the present disclosure can be determined and optimized by the skilled artisan, e.g., by observation of the patient, including the patient's overall health, the response to the combination therapy, and the like. Optimization, for example, may be necessary if it is determined that a patient is not exhibiting the desired therapeutic effect or conversely, if the patient is experiencing undesirable or adverse side effects that are too many in number or are of a troublesome severity.

It is especially advantageous to formulate compositions of the present disclosure in unit dosage form for ease of administration and uniformity of dosage. The specifications of the dosage unit forms of the present disclosure are dependent on the unique characteristics of the composition and the particular therapeutic effect to be achieved. Dosages can further be determined by reference to the usual dose and manner of administration of the ingredients. Suitable pharmaceutical compositions and dosage forms may be prepared using conventional methods known to those in the field of pharmaceutical formulation and described in the pertinent texts and literature, e.g., in Remington: The Science and Practice of Pharmacy (Easton, Pa.: Mack Publishing Co., 1995).

Examples

Fatty Acid Derivatives

Step 1: Synthesis of 2-oxopropane-1,3-diyl dioctanoate (3): To an ice cold solution of 1,3-dihydroxypropan-2-one (1, 25.0 g, 0.277 mol) in dichloromethane (500 mL) was added 4-dimethylaminopyridine (10.17 g, 0.083 mol) and pyridine (49.2 mL, 0.610 mol) and stirred for next 5 min. To the above mixture octanoyl chloride (2, 105.4 mL, 0.610 mol) was added dropwise at 0° C., and the reaction mixture was stirred at room temperature for 16 h. After completion, reaction mixture was filtered; the solid was washed with dichloromethane (100 mL), filtrate was washed with brine (200 mL), saturated solution of sodium bicarbonate (200 mL) and 0.1 N HCl solution (100 mL). Organic layer was separated and dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to get crude. The crude was purified by silica gel (100-200 mesh) column chromatography eluting with 10% ethyl acetate in hexanes to afford the desired product as white solid. Yield: 70.0 g, 73%. MS (ESI) m/z 343.19[M+1]⁺; ¹H NMR (400 MHz, DMSO-d6); δ 4.84 (s, 4H), 2.37 (t, J=7.2 Hz, 4H), 1.45-1.62 (m, 4H), 1.15-1.35 (m, 16H), 0.78-0.92 (m, 6H).

Step 2: Synthesis of 2-hydroxypropane-1,3-diyl dioctanoate (4): To an ice cold solution of 2-oxopropane-1,3-diyl dioctanoate (3, 70.0 g, 0.204 mol) in THF (1000 mL) was added drop wise acetic acid (15 mL), followed by the portion wise addition of sodium cyanoborohydride (15.43 g, 0.245 mol). The reaction mixture was stirred at room temperature for 16 h. After completion, reaction mixture was diluted with water (400 mL) and extracted with ethyl acetate (3×200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and solvent was removed under reduced pressure. The crude thus obtained was purified by silica gel (100-200 mesh) column chromatography eluting with 12 to 15% ethyl acetate in hexanes to afford the desired product 4 as yellow liquid. Yield: 50.0 g, 71%. MS (ESI)− m/z 345.29[M+1]⁺; ¹H NMR (400 MHz, DMSO-d6); δ 5.25 (d, J=5.2 Hz, 1H), 3.92-4.03 (m, 4H), 3.81-3.90 (m, 1H), 2.29 (t, J=7.6 Hz, 4H), 1.45-1.59 (m, 4H), 1.12-1.35 (m, 16H), 0.85 (t, J=6.8 Hz, 6H).

Step 3: Synthesis of 4-((1,3-bis(octanoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid (6): To a solution of 2-hydroxypropane-1,3-diyl dioctanoate (4, 50.0 g, 0.145 mol) in chloroform (200 mL), dihydrofuran-2,5-dione (5, 17.44 g, 0.174 mol) and triethylamine (30.0 mL, 0.218 mol) were added at room temperature. The reaction mixture was stirred at 120° C. for 3 h. After completion, reaction mixture was diluted with water (200 mL) and extracted with 1,2 dichloromethane (3×200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude thus obtained was purified by silica gel (100-200 mesh) column chromatography eluting with 10 to 15% ethyl acetate in hexanes to afford the desired product 6 as white solid. Yield: 47.0 g, 72%. MS (ESI)− m/z 443.2[M−1]; ¹H NMR (400 MHz, DMSO-d6): δ 12.22 (s, 1H), 5.12-5.22 (m, 1H), 4.18-4.25 (m, 2H), 4.09-4.17 (m, 2H), 2.42-2.50 (m, 4H), 2.29 (t, J=7.24 Hz, 4H), 1.44-1.55 (m, 4H), 1.15-1.31 (m, 16H), 0.79-0.90 (m, 6H).

Step 1: Synthesis of 2-oxopropane-1,3-diyl didodecanoate (3A): To an ice cold solution of 1,3-dihydroxypropan-2-one (1, 30.0 g, 0.33 mol) in dichloromethane (500 mL) was added 4-dimethylaminopyridine (20.30 g, 0.167 mol) and pyridine (107 mL, 0.1.332 mol) and stirred for next 5 min. To the above mixture dodecanoyl chloride 2A (218.50 g, 1.167 mol) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 16 h. After completion, reaction mixture was filtered; the solid was washed with dichloromethane (100 mL), filtrate was washed with brine (200 mL), saturated solution of sodium bicarbonate (200 mL) and 0.1 N HCl solution (100 mL). Organic layer was separated and dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to get crude. The crude was triturated with diethyl ether to afford the desired product 3A as white solid. Yield: 78 g, 51%. MS (ESI) m/z 455.37[M+1]⁺; ¹H NMR (400 MHz, DMSO-d6) −δ 4.74 (s, 4H), 2.43 (m, 4H), 1.64 (m, 4H), 1.55-1.25 (m, 32H), 0.87 (m, 6H).

Step 2: Synthesis of 2-hydroxypropane-1,3-diyl didodecanoate (4A): To an ice cold solution of 2-oxopropane-1,3-diyl didodecanoate 3A (75.0 g, 0.165 mol) in THF (1000 mL) was added drop wise acetic acid (15 mL) followed by the portion wise addition of sodium cyanoborohydride (12.41 g, 0.198 mol). The reaction mixture was stirred at room temperature for 16 h. After completion, reaction mixture was diluted with water (400 mL) and extracted with ethyl acetate (3×200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and solvent was removed under reduced pressure. The crude was triturated with diethyl ether to afford the desired product 4A as white solid. Yield: 60.0 g, 80%. MS (ESI); m/z 457.48[M+1]⁺; ¹H NMR (400 MHz, DMSO-d6) −δ 5.26 (d, J=5.2 Hz, 1H), 3.92-3.98 (m, 4H), 2.28 (m, 4H), 1.50 (m, 4H), 1.23 (m, 33H), 0.83 (m, 6H).

Step 3: Synthesis of 4-((1,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid (6A): To a solution of 2-hydroxypropane-1,3-diyl didodecanoate 4A (40.0 g, 0.087 mol) in chloroform (200 mL), dihydrofuran-2,5-dione 5 (10.50 g, 0.105 mol) and triethylamine (18.50 mL, 0.131 mol) were added at room temperature. The reaction mixture was stirred at 120° C. for 3 h. After completion, reaction mixture was diluted with water (200 mL) and extracted with 1,2 dichloromethane (3×200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude thus obtained was purified by silica gel (100-200 mesh) column chromatography eluting with 25 to 30% ethyl acetate in hexanes to afford the desired product 6A as white solid. Yield: 20.0 g, 41%. MS (ESI) m/z 555.40[M−1]; ¹H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 5.17 (m, 1H), 4.18-4.25 (m, 4H), 2.50-2.47 (m, 8H), 1.23-1.25 (m, 36H), 0.83 (m, 6H).

Step 1—Synthesis of 2-oxopropane-1,3-diyl didodecanoate (3*): To an ice cold solution of 1,3-dihydroxypropan-2-one (1, 30.0 g, 0.33 mol) in dichloromethane (500 mL) was added 4-dimethylaminopyridine (20.30 g, 0.167 mol) and pyridine (107 mL, 0.1.332 mol) and stirred for next 5 min. To the above reaction mixture dodecanoyl chloride 2 (218.50 g, 1.167 mol) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 16 h. After completion, reaction mixture was filtered, the solid was washed with dichloromethane (100 mL), filtrate was washed with brine (200 mL), saturated solution of sodium bicarbonate (200 mL) and 0.1 N HCl solution (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to get crude. The crude was triturated with diethyl ether to afford the desired product 3* as white solid. Yield: 78 g, 51%. MS (ESI) m/z 455.37[M+1]+; 1H NMR (400 MHz, DMSO-d6): δ 4.74 (s, 4H), 2.43 (m, 4H), 1.64 (m, 4H), 1.55-1.25 (m, 32H), 0.87 (m, 6H).

Step-2: Synthesis of 2-hydroxypropane-1,3-diyl didodecanoate (4*): To an ice cold solution of 2-oxopropane-1,3-diyl didodecanoate 3 (75.0 g, 0.165 mol) in THF (1000 mL) was added drop wise acetic acid (15 mL) followed by the portion wise addition of sodium cyanoborohydride (12.41 g, 0.198 mol). The reaction mixture was stirred at room temperature for 16 h. After completion, reaction mixture was diluted with water (400 mL) and extracted with ethyl acetate (3×200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and solvent was removed under reduced pressure. The crude was triturated with diethyl ether to afford the desired product 4* as white solid. Yield: 60.0 g, 80%. MS (ESI) m/z 457.48[M+1]⁺; 1H NMR (400 MHz, DMSO-d6): δ 5.26 (d, J=5.2 Hz, 1H), 3.92-3.98 (m, 4H), 2.28 (m, 4H), 1.50 (m, 4H), 1.23 (m, 33H) and 0.83 (m, 6H).

Step-3: Synthesis of (E)-4-((1,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2-enoic acid (6*): To an ice-cold solution of 2-hydroxypropane-1,3-diyl didodecanoate 4 (10.0 g, 21.91 mmol) in THF (170 mL) was added fumaric acid 5 (2.54 g, 21.91 mmol), benzoyl chloride (2.5 mL, 21.91 mmol) and DMAP (0.67 g, 5.477 mmol). The resulting mixture was stirred at RT for 16 h. After completion of reaction (TLC monitoring), reaction mixture was concentrated under reduced pressure. The crude was diluted with water (200 mL), adjust pH ˜2-3 using 1N—HCl and extracted with 1,2 dichloromethane (3×200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude thus obtained was purified by silica gel (100-200 mesh) column chromatography eluting with 80% ethyl acetate in hexanes to afford the desired product 6* as white solid. Yield: 400 mg, 3.30% (un-optimized yield). LC-MS: m/z 553.64[M−1]; 97.27% purity. 1H NMR (400 MHz, DMSO-d6): δ 13.26 (br s, 1H), 5.17 (d, J=15.8 Hz, 2H), 5.29 (m, 1H), 4.30-4.33 (m, 2H), 4.19-4.23 (m, 2H), 2.28 (m, 4H), 1.48 (m, 4H), 1.22 (m, 32H) and 0.83 (m, 6H).

Non-Limiting Exemplary Compositions

Batch ACGCP300220007B

TABLE 1 Composition for Lidocaine and Melatonin Lozenges Ingredients mg/Unit % w/w Granulation Xylitol 334.00 51.38 L-Carnosine 10.00 1.54 Heavy magnesium oxide 25.00 3.85 Calcium carbonate 25.00 3.85 CCS 5.00 0.77 Binder solution Hypromellose 5 cps 10.00 1.54 Simethicone 25.00 3.85 Water q.s — Extra granular Lidocaine 100.00 15.38 Melatonin 10.00 1.54 Xylitol 300 85.00 13.08 CCS 5.00 0.77 Colloidal Silicon Dioxide 3.00 0.46 Zinc stearate 6.50 1.00 Peppermint flavor 6.50 1.00 Avg tablet weight 650.00 100.00

Method of Preparation of Lidocaine and Melatonin Lozenge

I. Granulation

-   -   i. Step 1—Dispensing: Dispensed all the required raw materials         using a calibrated weighing balance.     -   ii. Step 2—Sifting: Xylitol, L-Carnosine, Magnesium oxide,         Calcium carbonate, L-Carnosine, Hypromellose, Croscarmellose         sodium, and simethicone powder were sifted and passed through         ASTM #40 sieve.     -   iii. Step 3—Dry mixing: The sifted mixture was dry mixed in         Rapid Mixer Granulator for 10 min at 50 RPM.     -   iv. Step 4—Binder solution preparation: Hypromellose 5 cps was         dissolved in water and mixed well followed by the addition of         Simethicone.     -   v. Step 5—Wet Mixing: The dry mix obtained in step 3 was         granulated using binder solution prepared in step 4 to obtain         granules.     -   vi. Step 6—Drying: Granules obtained in step 5 were dried at an         inlet temperature of NMT 60° C. until LOD of NMT 4.5% is         obtained.     -   vii. Step 7—Sizing: Dried granules were passed through ASTM         sieve no. 40.     -   viii. Step 8—Pre-Lubrication: Granules of step 7 were blended         with extra-granular materials (passed through ASTM 40 sieve)         i.e., Lidocaine, Melatonin, Xylitol 300, Croscarmellose sodium         (CCS), colloidal silicon dioxide and peppermint flavor and         blended for 10 min.     -   ix. Step 9—Lubrication: Blend obtained in step 8 was lubricated         with #60 passed zinc stearate for 5 min.

II. Compression:

Lubricated blend obtained in step 9 was compressed. Compression parameters are provided in Table 2 below:

TABLE 2 Compression parameters Parameter Observations Tablet weight (mg) 650 Hardness (kP) 5-6 kp Thickness (mm) 5.05-5.15 Disintegration time (min) 8-9 min Remarks No sticking observed, flow of blend was good

III. Packaging:

The obtained tablets were packed in 60 cc HDPE bottle along with one 2 g silica gel bag, induction sealed and closed with 33 mm CR closure.

IV. Dissolution Study:

Dissolution profile of the lozenges were tested, results whereof are provided in Table 3 below.

TABLE 3 Dissolution profile of lozenges Initial Lidocaine Melatonin Time Average Average  5 Min 17 10  10 Min 27 20  15 Min 36 30  30 Min 54 49  45 Min 63 59  60 Min 66 63  90 min 71 69 120 min 76 74 Infinity 102 97

Batch ACGCP300220008B

Lozenges were prepared using the composition as provided in Table 4 below.

TABLE 4 Composition for Lidocaine and Melatonin Lozenges Ingredients mg/Unit % w/w Granulation Xylitol 90 239.00 45.07 L-Carnosine 10.00 1.89 Heavy magnesium oxide 25.00 4.72 Calcium carbonate 25.00 4.72 Croscarmellose sodium 5.00 0.94 Binder solution Hypromellose 5 cps 10.00 1.89 Simethicone 25.00 4.72 Water q.s q.s Extra granular Lidocaine hydrochloride monohydrate 100.00 18.87 Melatonin 10.00 1.89 Xylitol 300 10.00 1.89 D-Panthenol 50.00 9.43 Croscarmellose sodium 5.00 0.94 Colloidal Silicon Dioxide 3.00 0.57 Zinc stearate 6.50 1.23 Peppermint flavor 6.50 1.23 Average tablet weight 530.00 100.00

Batch ACGCP300220009B

Lozenges were prepared using the composition as provided in Table 5 below:

TABLE 5 Composition for Lidocaine and Melatonin Lozenges Ingredients mg/Unit % w/w Granulation Xylitol 90 576.00 57.60 L-Carnosine 10.00 1.00 Heavy magnesium oxide 25.00 2.50 Calcium carbonate 25.00 2.50 Croscarmellose sodium 7.00 0.70 Citric acid 99.17 9.92 Colloidal Silicon Dioxide 26.00 2.60 Binder solution Hypromellose 5 cps 10.00 1.00 Citric acid 0.83 0.08 D Panthenol 50.00 5.00 Simethicone 25.00 2.50 Water q.s — Extra granular Lidocaine Hydrochloride Monohydrate 100.00 10.00 Melatonin 10.00 1.00 Xylitol 300 10.00 1.00 Croscarmellose sodium 13.00 1.30 Zinc stearate 6.50 0.65 Peppermint flavor 6.50 0.65 Average tablet weight 1000.00 100.00 Note: Intra-granular material formed was sticky and rubbery

Batch ACGCP300220010B

Lozenges were prepared using the composition as provided in Table 6 below. Direct compression was used for preparation of the lozenges.

TABLE 6 Composition for Lidocaine and Melatonin Lozenges Ingredients mg/Unit % w/w Xylitol 300 287.21 44.19 L-Carnosine 10.00 1.54 Heavy magnesium oxide 25.00 3.85 Calcium carbonate 25.00 3.85 CCS 20.00 3.08 Citric acid 100.00 15.38 Hypromellose 5 cps 10.00 1.54 Simethicone 30% 25.00 3.85 Lidocaine 100.00 15.38 Melatonin 10.00 1.54 Cal D-Panthenol (D-Panthenol) 21.54 3.31 Aerosil 3.25 0.50 Zinc stearate 6.50 1.00 Peppermint flavor 6.50 1.00 Avg tablet weight 650.00 100.00

Method of Preparation of Lidocaine and Melatonin Lozenge

-   -   i. Step 1—Dispensing: Dispensed all the required raw materials         using a calibrated weighing balance.     -   ii. Step 2—Sifting: Xylitol, L-Carnosine, Magnesium oxide,         Calcium carbonate, L-Carnosine, Hypromellose, Croscarmellose         sodium, and citric acid were sifted and passed through ASTM #40         sieve.     -   iii. Step 3—Dry mixing: The sifted mixture was dry mixed in         Rapid Mixer Granulator for 10 min at 50 RPM. Simethicone was         added to mixture and mixed well.     -   iv. Step 4—Drying: the wet mass was dried at an inlet         temperature of NMT 60° C. until LOD of NMT 3.5% was obtained.     -   v. Step 5—Sizing: Dried material of step 4 was passed through         ASTM sieve no. 40.     -   vi. Step 6—Pre-Lubrication: Material from step 5 were blended         with other materials (passed through ASTM 40 sieve) i.e.,         Lidocaine, melatonin, Calcium D-Pantothenate, colloidal silicon         dioxide and peppermint flavor and blended for 10 min.     -   vii. Step 7—Lubrication: Blend of step 7 was lubricated with #60         passed zinc stearate for 5 min.     -   viii. Step 8: Lubricated blend of step 7 was compressed with         compression parameters as provided in Table below. Storage: 40         lozenges were filled in 60 cc HDPE bottle along with one 2 g         silica gel bag, induction sealed and closed with 33 mm CR         closure.

TABLE 7 Compression parameters Parameter Observations Tablet weight (mg) 650 Hardness (kP) 5-6 Thickness (mm) 5.05-5.15 Disintegration time (min) 8-9 Remarks The disintegration time of the lozenges were observed to be faster.

Batch ACGCP300220006B

Lozenges were prepared using the composition as provided in Table 8 below. Lozenges were prepared by direct compression, process whereof has been described in detail in the previous example.

TABLE 8 Composition for Lidocaine and Melatonin Lozenges Ingredients mg/Unit % w/w Xylitol 300 237.21 36.49 L-Carnosine 10.00 1.54 Heavy magnesium oxide 25.00 3.85 Calcium carbonate 25.00 3.85 Croscarmellose sodium 20.00 3.08 Citric acid 100.00 15.38 Hypromellose 5 cps 10.00 1.54 Simethicone 30% 25.00 3.85 Lidocaine hydrochloride monohydrate 100.00 15.38 Melatonin 10.00 1.54 Cal D-Panthenol (D-Panthenol) 21.54 3.31 N-Acetyl cysteine 50.00 7.69 Colloidal silicon dioxide 3.25 0.50 Zinc stearate 6.50 1.00 Peppermint flavor 6.50 1.00 Average tablet weight 650.00 100.00

TABLE 9 Compression parameters Toolings 13 mm round Average tablet weight (mg) 650.0 Tablet hardness (kP) 4-6 Disintegration time (min) 7-8 Tablet thickness (mm) 4.8-4.9 Remarks The disintegration time of the lozenges were observed to be faster.

Batch ACGCP300220012B

Lozenges were prepared using the composition as provided in Table 10 below. Lozenges were prepared by direct compression, using the process described in detail in the previous example.

TABLE 10 Composition for Lidocaine and Melatonin Lozenges Ingredients mg/Unit % w/w Xylitol 300 297.21 45.72 L-Carnosine 10.00 1.54 Heavy magnesium oxide 25.00 3.85 Calcium carbonate 25.00 3.85 Croscarmellose sodium 10.00 1.54 Citric acid 100.00 15.38 Hypromellose 5 cps 10.00 1.54 Simethicone 30% 25.00 3.85 Lidocaine hydrochloride monohydrate 100.00 15.38 Melatonin 10.00 1.54 Cal D-Panthenol (D-Panthenol) 21.54 3.31 Colloidal silicondioxide 3.25 0.50 Zinc stearate 6.50 1.00 Peppermint flavor 6.50 1.00 Average tablet weight 650.00 100.00

TABLE 11 Compression parameters Parameter Observations Toolings 13 mm round Average tablet weight (mg) 650.0 Tablet hardness (kP) 6-7 Disintegration time (min) 7-8 Tablet thickness (mm) 4.9-5.0 Remarks The disintegration time of the lozenges was not retarded with removal of disintegrant

Batch ACGCP300220013B

Lozenges were prepared using the composition as provided in Table 12 below. Lozenges were prepared by direct compression, using the process described in detail in the previous example.

TABLE 12 Composition for Lidocaine and Melatonin Lozenges Ingredients mg/Unit % w/w Xylitol 300 281.21 43.26 L-Carnosine 10.00 1.54 Heavy magnesium oxide 25.00 3.85 Calcium carbonate 25.00 3.85 Croscarmellose sodium 10.00 1.54 Citric acid 100.00 15.38 Hypromellose 5cps 26.00 4.00 Simethicone 30% 25.00 3.85 Lidocaine hydrochloride monohydrate 100.00 15.38 Melatonin 10.00 1.54 Cal D-Panthenol (D-Panthenol) 21.54 3.31 Colloidal silicon dioxide 3.25 0.50 Zinc stearate 6.50 1.00 Peppermint flavor 6.50 1.00 Average tablet weight 650.00 100.00

TABLE 13 Compression parameters Parameter Observations Toolings 13 mm round Average tablet weight (mg) 650.0 Tablet hardness (kP) 6-7 Disintegration time (min) 7-8 Tablet thickness (mm) 4.9-5.0 Remarks The disintegration time of the lozenges was not retarded with increase of binder concentration

Batch ACGCP300220014B

Lozenges were prepared using the composition as provided in Table 14 below. Lozenges were prepared by direct compression, using the process described in detail in the previous example.

TABLE 14 Composition for Lidocaine and Melatonin Lozenges Ingredients mg/Unit % w/w Xylitol 300 281.21 43.26 L-Carnosine 10.00 1.54 Heavy magnesium oxide 25.00 3.85 Calcium carbonate 25.00 3.85 Croscarmellose sodium 10.00 1.54 Citric acid 100.00 15.38 Hypromellose 15cps 26.00 4.00 Simethicone 30% 25.00 3.85 Lidocaine hydrochloride monohydrate 100.00 15.38 Melatonin 10.00 1.54 Cal D-Panthenol (D-Panthenol) 21.54 3.31 Colloidal silicon dioxide 3.25 0.50 Zinc stearate 6.50 1.00 Peppermint flavor 6.50 1.00 Average tablet weight 650.00 100.00

TABLE 15 Compression parameters Parameter Observations Toolings 13 mm round Average tablet weight (mg) 650.0 Tablet hardness (kP) 5-6 Disintegration time (min) 7-8 Tablet thickness (mm) 4.9-5.0 Remarks The disintegration time of the lozenges was not retarded with change in the grade of binder

Batch ACGCP300220015B

Lozenges were prepared using the composition as provided in Table 16 below. Lozenges were prepared by direct compression, using the process described in detail in the previous example.

TABLE 16 Composition for Lidocaine and Melatonin Lozenges Ingredients mg/Unit % w/w Xylitol 300 281.21 43.26 L-Carnosine 10.00 1.54 Heavy magnesium oxide 25.00 3.85 Calcium carbonate 25.00 3.85 Croscarmellose sodium 10.00 1.54 Citric acid 100.00 15.38 Hypromellose 15cps 26.00 4.00 Simethicone powder 25.00 3.85 Lidocaine hydrochloride monohydrate 100.00 15.38 Melatonin 10.00 1.54 Cal D-Panthenol (D-Panthenol) 21.54 3.31 Colloidal silicon dioxide 3.25 0.50 Zinc stearate 6.50 1.00 Peppermint flavor 6.50 1.00 Average tablet weight 650.00 100.00

TABLE 17 Compression parameters Parameter Observations Toolings 13 mm round Average tablet weight (mg) 650.0 Tablet hardness (kP) 3-4 Disintegration time (min)  9-10 Tablet thickness 5.22-5.30 Remarks The disintegration time of the lozenges was not retarded with change in the grade of binder

Batch ACGCP300220016B1

Lozenges were prepared using the composition as provided in Table 18 below. Lozenges were prepared by direct compression, using the process described in detail in the previous example.

TABLE 18 Composition for Lidocaine and Melatonin Lozenges Ingredients mg/Unit % w/w Mannitol 284.71 43.80 L-Carnosine 10.00 1.54 Heavy magnesium oxide 25.00 3.85 Calcium carbonate 25.00 3.85 Croscarmellose sodium 5.00 0.77 Citric acid 100.00 15.38 Hypromellose E50cps 32.50 5.00 Simethicone powder 25.00 3.85 Lidocaine hydrochloride monohydrate 100.00 15.38 Melatonin 10.00 1.54 Cal D-Panthenol (D-Panthenol) 21.54 3.31 Colloidal silicon dioxide 3.25 0.50 Zinc stearate 6.50 1.00 Peppermint flavor 6.50 1.00 Average tablet weight 655.00 100.77

TABLE 19 Compression parameters Parameter Observations Toolings 13 mm round Average tablet weight (mg) 655.0 Tablet hardness (kP) 4-5 Disintegration time (min) 11-13 Remarks The disintegration time of the lozenges was not significantly retarded with change in the grade of binder

Batch ACGCP300220016B2

Lozenges were prepared using the composition as provided in Table 20 below. Lozenges were prepared by direct compression, using the process described in detail in the previous example.

TABLE 20 Composition for Lidocaine and Melatonin Lozenges Ingredients mg/Unit % w/w Mannitol 284.71 43.80 L-Carnosine 10.00 1.54 Heavy magnesium oxide 25.00 3.85 Calcium carbonate 25.00 3.85 Citric acid 100.00 15.38 Hypromellose E50cps 32.50 5.00 Simethicone powder 25.00 3.85 Lidocaine hydrochloride monohydrate 100.00 15.38 Melatonin 10.00 1.54 Cal D-Panthenol (D-Panthenol) 21.54 3.31 Colloidal silicon dioxide 3.25 0.50 Zinc stearate 6.50 1.00 Peppermint flavor 6.50 1.00 Average tablet weight 650.00 100.00

TABLE 21 Compression parameters Parameter Observations Toolings 13 mm round Average tablet weight (mg) 650.0 Tablet hardness (kP) 4-5 Disintegration time (min) 11-13 Remarks The disintegration time of the lozenges was not retarded with removal of disintegrant

Batch ACGCP300220017B

Lozenges were prepared using the composition as provided in Table 22 below. Lozenges were prepared by direct compression, using the process described in detail in the previous example.

TABLE 22 Composition for Lidocaine and Melatonin Lozenges Ingredients mg/Unit % w/w Mannitol 284.71 43.80 L-Carnosine 10.00 1.54 Heavy magnesium oxide 25.00 3.85 Calcium carbonate 25.00 3.85 Croscarmellose sodium 0.00 0.00 Citric acid 100.00 15.38 Hypromellose K4M 32.50 5.00 Simethicone 30% powder 25.00 3.85 Lidocaine 100.00 15.38 Melatonin 10.00 1.54 Cal D-Panthenol (D-Panthenol) 21.54 3.31 Colloidal silicon dioxide 3.25 0.50 Zinc stearate 6.50 1.00 Peppermint flavor 6.50 1.00 Average tablet weight 650.00 100.00

TABLE 23 Compression parameters Parameter Observations Toolings 13 mm round Average tablet weight (mg) 650.0 Tablet hardness (kP) 8-9 Disintegration time (min) 10-11 Tablet thickness (mm) 5.02-5.10 Remarks The disintegration time of the lozenges was not retarded with change in the grade of binder

Batch ACGCP300220018B

Lozenges were prepared using the composition as provided in Table 24 below. Lozenges were prepared by direct compression, using the process described in detail in the previous example.

TABLE 24 Composition for Lidocaine and Melatonin Lozenges Ingredients mg/Unit % w/w Xylitol 282.21 43.42 DGLF 5.00 0.77 L-Carnosine 10.00 1.54 Heavy magnesium oxide 25.00 3.85 Calcium carbonate 25.00 3.85 Croscarmellose sodium 20.00 3.08 Citric acid monohydrate 100.00 15.38 Hypromellose 5cps 10.00 1.54 Simethicone 30% powder 25.00 3.85 Lidocaine hydrochloride monohydrate 100.00 15.38 Melatonin 10.00 1.54 Cal D-Panthenol (D-Panthenol) 21.54 3.31 Colloidal silicon dioxide 3.25 0.50 Zinc stearate 6.50 1.00 Peppermint flavor 6.50 1.00 Average tablet weight 650.00 100.00

TABLE 25 Compression parameters Parameter Observations Toolings 13 mm round Average tablet weight (mg) 650.0 Tablet hardness (kP) 3-5 Tablet thickness (mm) 4.98-5.12 Disintegration time (min) 8-9 Remarks The DGLF had no impact on tablet properties. The dissolution was found to be satisfactory

TABLE 26 Dissolution in pH 6.8 Phosphate buffer Initial Lidocaine Melatonin Time Average Average   5 Min 45 40  10 Min 76 68  15 Min 94 85  30 Min 102 91  45 Min 102 92  60 Min 102 92  90 min 101 92 120 min 102 92 Infinity 102 92

Batch ACGCP300220019B

Lozenges were prepared using the composition as provided in Table 27 below. Lozenges were prepared by direct compression, using the process described in detail in the previous example.

TABLE 27 Composition for Lidocaine and Melatonin Lozenges Ingredients Granulation mg/Unit % w/w Xylitol 278.96 42.92 DGLF 5.00 0.77 L-Carnosine 10.00 1.54 Heavy magnesium oxide 25.00 3.85 Calcium carbonate 25.00 3.85 CCS 20.00 3.08 Citric acid 100.00 15.38 Hypromellose 5 cps 10.00 1.54 Simethicone 30% powder 25.00 3.85 Lidocaine 100.00 15.38 Melatonin 10.00 1.54 Cal D-Panthenol (D-Panthenol) 21.54 3.31 Aerosil 6.50 1.00 Zinc stearate 6.50 1.00 Peppermint flavor 6.50 1.00 Avg tablet weight 650.00 100.00

TABLE 28 Compression parameters Parameter Observations Toolings 13 mm round Average tablet weight (mg) 650.0 Tablet hardness (kP) 5-6 Tablet thickness (mm) 5.05-5.10 Disintegration time (min) 7-9 Remarks Sticking observed, flow of blend was good

TABLE 29 Physico-chemical properties Test Results Assay of Lidocaine (%) 102.2 Assay of Melatonin (%) 102.3 Water content (% w/w) 3.5 Related substances Lidocaine IMP-H 0.002 Melatonin IMP-A 0.002 Any unknown highest of Lido @ 0.559 0.002 Any unknownhighest of Mela @0.812 0.007 Total Impurities 0.023 Dissolution of tablets in pH 6.8 Phosphate buffer Lidocaine 5 min 44 10 min 73 15 min 90 30 min 98 45 min 98 60 min 98 90 min 99 120 min 99 INF 99 Melatonin 5 min 44 10 min 73 15 min 92 30 min 102 45 min 102 60 min 102 90 min 103 120 min 103 INF 103

Batch ACGCP300220020B

Lozenges were prepared using the composition as provided in Table 30 below. Lozenges were prepared by direct compression, using the process described in detail in the previous example.

TABLE 30 Composition for Lidocaine and Melatonin Lozenges Ingredients mg/Unit % w/w Xylitol 285.96 43.99 DGLF 5.00 0.77 L-Carnosine 10.00 1.54 Heavy magnesium oxide 25.00 3.85 Calcium carbonate 25.00 3.85 CCS 20.00 3.08 Citric acid 100.00 15.38 Hypromellose 5 cps 10.00 1.54 Simethicone 30% powder 25.00 3.85 Lidocaine 100.00 15.38 Melatonin 3.00 0.46 Cal D-Panthenol (D-Panthenol) 21.54 3.31 Aerosil 6.50 1.00 Zinc stearate 6.50 1.00 Peppermint flavor 6.50 1.00 Avg tablet weight 650.00 100.00

TABLE 31 Compression parameters Parameter Observations Toolings 13 mm round Average tablet weight (mg) 650.0 Tablet hardness (kP) 4-6 Disintegration time (min) 7-9 Remarks Flow of blend was good

TABLE 32 Dissolution in pH 6.8 Phosphate buffer Initial Lidocaine Melatonin Time Average Average 5 Min 43 40 10 Min 74 69 15 Min 92 87 30 Min 103 98 45 Min 103 98 60 Min 103 99 90 min 103 99

Batch ACGCP300220021B

Lozenges were prepared using the composition as provided in Table 33 below. Lozenges were prepared by direct compression, using the process described in detail in the previous example.

TABLE 33 Composition for Lidocaine and Melatonin Lozenges Ingredients Granulation mg/Unit % w/w Xylitol 290.96 44.76 L-Carnosine 10.00 1.54 Heavy magnesium oxide 25.00 3.85 Calcium carbonate 25.00 3.85 CCS 20.00 3.08 Citric acid 100.00 15.38 Hypromellose 5 cps 10.00 1.54 Simethicone 30% powder 25.00 3.85 Lidocaine 100.00 15.38 Melatonin 3.00 0.46 Cal D-Panthenol (D-Panthenol) 21.54 3.31 Aerosil 6.50 1.00 Zinc stearate 6.50 1.00 Peppermint flavor 6.50 1.00 Avg tablet weight 650.00 100.00

TABLE 34 Compression parameters Parameter Observations Toolings 13 mm round Average tablet weight (mg) 650.0 Tablet hardness (kP) 4-6 Disintegration time (min) 7-9 Remarks Flow of blend was good

TABLE 35 Dissolution in pH 6.8 Phosphate buffer Initial Lidocaine Melatonin Time Average Average 5 Min 47 43 10 Min 80 75 15 Min 99 94 30 Min 104 100 45 Min 105 100 60 Min 104 100 90 min 105 100

Batch ACGCP300220022B

Lozenges were prepared using the composition as provided in Table 36 below. Lozenges were prepared by direct compression, using the process described in detail in the previous example.

TABLE 36 Composition for Lidocaine and Melatonin Lozenges Ingredients Granulation mg/Unit % w/w Xylitol 285.96 43.99 DGLF 5.00 0.77 L-Carnosine 10.00 1.54 Heavy magnesium oxide 25.00 3.85 Calcium carbonate 25.00 3.85 CCS 20.00 3.08 Citric acid 100.00 15.38 Hypromellose 5 cps 10.00 1.54 Simethicone 30% emulsion 25.00 3.85 Lidocaine 100.00 15.38 Melatonin 3.00 0.46 Cal D-Panthenol (D-Panthenol) 21.54 3.31 Aerosil 6.50 1.00 Zinc stearate 6.50 1.00 Peppermint flavor 6.50 1.00 Avg tablet weight 650.00 100.00

TABLE 37 Compression parameters Parameter Observations Toolings 13 mm round Average tablet weight (mg) 650.0 Tablet hardness (kP) 4-6  Disintegration time (min) 7-10 Remarks Flow of blend was good

TABLE 38 Physico-chemical parameters Initial Lidocaine Melatonin Assay 97.2 98.4 Dissolution in pH 6.8 Phosphate buffer Time Average Average 5 Min 49 47 10 Min 80 77 15 Min 97 94 30 Min 105 102 45 Min 105 101 60 Min 105 101 90 min 105 101

Batch ACGCP300220023B

Lozenges were prepared using the composition as provided in Table 39 below. Lozenges were prepared by direct compression, using the process described in detail in the previous example.

TABLE 39 Composition for Lidocaine and Melatonin Lozenges Ingredients Granulation mg/Unit % w/w Xylitol 290.96 44.76 L-Carnosine 10.00 1.54 Heavy magnesium oxide 25.00 3.85 Calcium carbonate 25.00 3.85 CCS 20.00 3.08 Citric acid 100.00 15.38 Hypromellose 5 cps 10.00 1.54 Simethicone 30% emulsion 25.00 3.85 Lidocaine 100.00 15.38 Melatonin 3.00 0.46 Cal D-Panthenol (D-Panthenol) 21.54 3.31 Aerosil 6.50 1.00 Zinc stearate 6.50 1.00 Peppermint flavor 6.50 1.00 Avg tablet weight 650.00 100.00

TABLE 40 Compression parameters Parameter Observations Toolings 13 mm round Average tablet weight (mg) 650.0 Tablet hardness (kP) 4-6  Disintegration time (min) 7-10 Remarks Flow of blend was good

TABLE 41 Physico-chemical parameters Initial Lidocaine Melatonin Assay 102.2 104.0 Dissolution in pH 6.8 Phosphate buffer Time Average Average 5 Min 49 46 10 Min 78 73 15 Min 92 87 30 Min 100 95 45 Min 102 97 60 Min 102 97 90 min 102 97

Batch ACGCP300220024B

Lozenges were prepared using the composition as provided in Table 42 below. Lozenges were prepared by direct compression, using the process described in detail in the previous example.

TABLE 42 Composition for Lidocaine and Melatonin Lozenges Ingredients Granulation mg/Unit % w/w Xylitol 290.96 44.76 L-Carnosine 10.00 1.54 Heavy magnesium oxide 25.00 3.85 Calcium carbonate 25.00 3.85 CCS 20.00 3.08 Citric acid 100.00 15.38 Hypromellose 5 cps 10.00 1.54 Simethicone 30% emulsion 25.00 3.85 Lidocaine 200.00 30.77 Melatonin 3.00 0.46 Cal D-Panthenol (D-Panthenol) 21.54 3.31 Aerosil 6.50 1.00 Zinc stearate 6.50 1.00 Peppermint flavor 6.50 1.00 Avg tablet weight 750.00 115.38

TABLE 43 Compression parameters Parameter Observations Toolings 13 mm round Average tablet weight (mg) 650.0 Tablet hardness (kP) 4-6  Disintegration time (min) 7-10 Remarks Flow of blend was good

TABLE 44 Dissolution in pH 6.8 Phosphate buffer Lidocaine Melatonin Time Average Average 5 Min 22 19 10 Min 40 36 15 Min 56 51 30 Min 88 83 45 Min 102 98 60 Min 103 100 90 min 103 100

Batch ACGCP200420001A

Lozenges were prepared using the composition as provided in Table 45 below. Lozenges were prepared by direct compression, using the process described in detail in the previous example.

TABLE 45 Composition for Lidocaine and Melatonin Lozenges Ingredients Granulation mg/Unit % w/w Xylitol 347.46 40.88 L-Carnosine 10.00 1.18 Heavy magnesium oxide 25.00 2.94 Calcium carbonate 25.00 2.94 CCS 40.00 4.71 Citric acid 100.00 11.76 Hypromellose 5 cps 10.00 1.18 Simethicone 30% emulsion 25.00 2.94 Lidocaine 200.00 23.53 Melatonin 3.00 0.35 Cal D-Panthenol (D-Panthenol) 21.54 2.53 Aerosil 30.00 3.53 Zinc stearate 6.50 0.76 Peppermint flavor 6.50 0.76 Avg tablet weight 850.00 100.00

TABLE 46 Compression parameters: Parameter Observations Toolings 13 mm round Average tablet weight (mg) 850.0 Tablet hardness (kP) 6-7  Disintegration time (min) 8-10 Remarks Flow of blend was good

TABLE 47 Dissolution of tablets in pH 6.8 Phosphate buffer Lidocaine Melatonin Time Average Average 5 Min 40 40 10 Min 70 69 15 Min 89 88 30 Min 101 102 45 Min 104 103 60 Min 104 103 INF 104 103

Batch ACGCP200420002A

Lozenges were prepared using the composition as provided in Table 48 below. Lozenges were prepared by direct compression, using the process described in detail in the previous example.

TABLE 48 Composition for Lidocaine and Melatonin Lozenges Ingredients Granulation mg/Unit % w/w Xylitol 342.46 40.29 L-Carnosine 10.00 1.18 Heavy magnesium oxide 25.00 2.94 Calcium carbonate 25.00 2.94 CCS 40.00 4.71 Citric acid 100.00 11.76 Hypromellose 5 cps 10.00 1.18 Simethicone 30% emulsion 25.00 2.94 DGLF 5.00 0.59 Lidocaine 200.00 23.53 Melatonin 3.00 0.35 Cal D-Panthenol (D-Panthenol) 21.54 2.53 Aerosil 30.00 3.53 Zinc stearate 6.50 0.76 Peppermint flavor 6.50 0.76 Avg tablet weight 850.00 100.00

TABLE 49 Compression parameters: Parameter Observations Toolings 13 mm round Average tablet weight (mg) 850.0 Tablet hardness (kP) 7-8  Disintegration time (min) 8-10 Remarks Flow of blend was good

TABLE 50 Dissolution of tablets in pH 6.8 Phosphate buffer Lidocaine Melatonin Time Average Average 5 Min 37 37 10 Min 68 69 15 Min 91 93 30 Min 102 104 45 Min 103 104 60 Min 102 102 INF 102 102

Batch ACGCP200420003B

Lozenges were prepared using the composition as provided in Table 51 below. Lozenges were prepared by direct compression, using the process described in detail in the previous example.

TABLE 51 Composition for Lidocaine and Melatonin Lozenges Ingredients Granulation mg/Unit % w/w Xylitol 390.96 60.15 L-Carnosine 10.00 1.54 Heavy magnesium oxide 25.00 3.85 Calcium carbonate 25.00 3.85 CCS 20.00 3.08 Hypromellose 5 cps 10.00 1.54 Simethicone 30% emulsion 25.00 3.85 Lidocaine 100.00 15.38 Melatonin 3.00 0.46 Cal D-Panthenol (D-Panthenol) 21.54 3.31 Aerosil 6.50 1.00 Zinc stearate 6.50 1.00 Peppermint flavor 6.50 1.00 Avg tablet weight 650.00 100.00

TABLE 52 Compression parameters: Parameter Observations Toolings 13 mm round Average tablet weight (mg) 650.0 Tablet hardness (kP) 2-3  Disintegration time (min) 8-10 Remarks Flow of blend was good

TABLE 53 Dissolution of tablets in pH 6.8 Phosphate buffer Lidocaine Melatonin Time Average Average 5 Min 5 7 10 Min 10 12 15 Min 16 18 30 Min 32 32 45 Min 48 47 60 Min 63 61 INF 101 95

Batch ACGCP200420004B

Lozenges were prepared using the composition as provided in Table 54 below. Lozenges were prepared by direct compression, using the process described in detail in the previous example.

TABLE 54 Composition for Lidocaine and Melatonin Lozenges Ingredients Granulation mg/Unit % w/w Xylitol 388.96 59.84 L-Carnosine 10.00 1.54 Heavy magnesium oxide 25.00 3.85 Calcium carbonate 25.00 3.85 CCS 20.00 3.08 Sodium hylauronate 2.00 0.31 Hypromellose 5 cps 10.00 1.54 Simethicone 30% emulsion 25.00 3.85 Lidocaine 100.00 15.38 Melatonin 3.00 0.46 Cal D-Panthenol (D-Panthenol) 21.54 3.31 Aerosil 6.50 1.00 Zinc stearate 6.50 1.00 Peppermint flavor 6.50 1.00 Avg tablet weight 650.00 100.00

TABLE 55 Compression parameters: Parameter Observations Toolings 13 mm round Average tablet weight (mg) 650.0 Tablet hardness (kP) 2-3     Disintegration time (min) 6-8 min Remarks Flow of blend was good

TABLE 56 Dissolution of tablets in pH 6.8 Phosphate buffer Lidocaine Melatonin Time Average Average 5 Min 5 6 10 Min 8 10 15 Min 11 13 30 Min 23 25 45 Min 35 36 60 Min 47 47 90 Min 69 69 120 Min 92 91 INF 101 97

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above. 

1. A pharmaceutical composition comprising: Lidocaine or salt or hydrates or solvates thereof and Melatonin thereof.
 2. The composition of claim 1, wherein the composition comprises Lidocaine or salt or hydrates or solvates thereof and Melatonin thereof in a weight ratio ranging from 1:1 to 400:1.
 3. The composition of claim 1, wherein the composition comprises Lidocaine or salt or hydrates or solvates thereof and Melatonin thereof in a weight ratio ranging from 5:1 to 150:1.
 4. The composition of claim 1, wherein Lidocaine or salt or hydrates or solvates thereof is present in an amount ranging from 50 mg to 400 mg.
 5. The composition of claim 1, wherein Melatonin thereof is present in an amount ranging from 1 mg to 60 mg.
 6. The composition of claim 1, wherein the composition further comprises a pharmaceutically acceptable excipient.
 7. The composition of claim 6, wherein the pharmaceutically acceptable excipient is selected from any or a combination of: a diluent, an anti-oxidant, a preservative, an alkalizing agent, a buffering agent, a disintegrant, a binder, an antifoaming agent, a solvent, a glidant, a lubricant, a flavoring agent, a sweetener, a coating agent, a rate controlling polymer or non-polymer, a zinc salt, a fatty acid or derivative thereof, an amino acid or metabolites or derivative thereof, a bulking agent, an antitacking agent, an emulsifier, a surfactant, a plasticizer and a stabilizer.
 8. The composition of claim 7, wherein the fatty acid derivative comprises any or a combination of: diglyceryl lauryl fumarate, diglyceryl lauryl succinate, and diglyceryl capryl succinate.
 9. The composition of claim 1, wherein the composition comprises an intragranular portion and an extra-granular portion, wherein the intra-granular portion comprises Lidocaine or salt or hydrates or solvates thereof, Melatonin thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises a pharmaceutically acceptable excipient.
 10. The composition of claim 1, wherein the composition comprises an intragranular portion and an extra-granular portion, wherein the intra-granular portion comprises a pharmaceutically acceptable excipient, and the extra-granular portion comprises Lidocaine or salt or hydrates or solvates thereof, Melatonin thereof and a pharmaceutically acceptable excipient.
 11. The composition of claim 1, wherein the composition comprises an intragranular portion and an extra-granular portion, wherein the intra-granular portion comprises Melatonin thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises Lidocaine or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient.
 12. The composition of claim 1, wherein the composition comprises an intragranular portion and an extra-granular portion, wherein the intra-granular portion comprises Lidocaine or salt or hydrates or solvates thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises Melatonin thereof and a pharmaceutically acceptable excipient.
 13. The composition of claim 1, wherein the composition comprises an intragranular portion and an extra-granular portion, and wherein the portions are compressed together to obtain any of a tablet dosage form and a Lozenge dosage form, optionally coated with a seal coat.
 14. The composition of claim 1, wherein the composition comprises an intragranular portion and an extra-granular portion, and wherein the intra-granular portion comprises a pharmaceutically acceptable excipient, and the extra-granular portion comprises Lidocaine hydrochloride monohydrate in an amount of 100 mg, Melatonin in an amount of 10 mg and a pharmaceutically acceptable excipient.
 15. The composition of claim 1, wherein the composition comprises Lidocaine hydrochloride monohydrate in an amount of 100 mg, Melatonin in an amount of 10 mg and a pharmaceutically acceptable excipient, said composition being a directly compressed lozenge formulation.
 16. The composition of claim 1, wherein the composition comprises Lidocaine hydrochloride monohydrate in an amount of 100 mg, Melatonin in an amount of 3 mg and a pharmaceutically acceptable excipient, said composition being a directly compressed lozenge formulation.
 17. The composition of claim 1, wherein the composition comprises Lidocaine hydrochloride monohydrate in an amount of 200 mg, Melatonin in an amount of 3 mg and a pharmaceutically acceptable excipient, said composition being a directly compressed lozenge formulation.
 18. A method of treating oral and gastrointestinal disorders in a patient in need thereof comprising administering to a subject a therapeutically effective amount of the pharmaceutical composition of claim
 1. 19. Use of the pharmaceutical composition of claim 1 in preparation of a medicament for the treatment of oral and gastrointestinal diseases in patient in need thereof. 